PROJECT SUMMARY/ABSTRACT Our primary objective is to identify novel and effective approaches to the prevention and treatment of Graves' ophthalmopathy (GO), the ocular disease linked to Graves' hyperthyroidism. Histopathologic changes within the GO orbit are striking and include accumulation of hyaluronic acid (HA) and edema, increased numbers of mature fat cells, and the presence of inflammatory cytokines and chemokines. The resultant tissue remodeling, once established, can at best be imperfectly reversed or modulated through surgical intervention or aggressive immunotherapy. Our studies of the pathogenesis and clinical expressions of GO over the past two decades have led to new insights into the cellular and molecular mechanisms underlying the ocular tissue changes seen in the disease. Our laboratory has recently established a role for thyrotropin receptor (TSHR) autoantibodies in the initiation of these changes. We are now poised to greatly increase the significance and impact of this work. The central hypotheses to be tested are that autoantibodies directed against the TSHR in GO orbital fibroblasts initiate and sustain the disease processes in these cells and that small-molecule ligand antagonists of this receptor can inhibit these effects. In addition, we suggest that patients at high risk for the development or progression of GO can be identified using novel biomarkers and by prospective study of hyperthyroid patients using currently obtainable clinical data. In this application, we will expand our studies concerning mechanisms involved in TSHR activation by stimulatory, neutral and blocking autoantibodies in GO (Aim 1). In addition, we will determine the ability of drug-like small molecule ligand antagonists of TSHR to block receptor activation, HA synthesis and adipogenesis in orbital fibroblasts. These studies will clarify the potential utility of these compounds as novel therapy. In Aim 2, we will identify new biomarkers of disease activity that might in future be used to identify high-risk patients. In Aim 3, we will develop a clinical prediction tool to identify at-risk patients in a prospective study using currently available patient data. The ability to reliably identify patients at high risk for GO onset or progression would have significant impact on the disease as these patients would benefit most from novel therapies aimed at preventing the tissue remodeling characteristic of established disease. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page